Apparatus and method for determining tissue characteristics

ABSTRACT

An apparatus and method embodying the invention include utilizing a device with a limited number of interrogation devices to accomplish a large number of measurements on a target tissue ( 50 ). An instrument embodying the invention includes a plurality of detection devices ( 54 ) that are arranged in a predetermined pattern on a tissue contacting face of the instrument. The face of the instrument is located adjacent the target tissue ( 50 ), and a plurality of tissue characteristic measurement are simultaneously conducted. The detection devices ( 54 ) are moved to a new position, preferably without moving the tissue contacting face, and a second plurality of tissue characteristic measurements are simultaneously conducted. By conducting a series of measurements cycles in this manner, the ultimate resolution of the device is increased, while still obtaining a given resolution, which reduces potential cross-talk errors. Further, a plurality of tissue characteristics are simultaneously obtained from locations spaced across the target tissue ( 50 ) during each measurement cycle.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention is related to apparatus and methods for determiningtissue characteristics within a body of a patient.

[0003] 2. Background of the Related Art

[0004] It is known to irradiate a target tissue with electromagneticradiation and to detect returned electromagnetic radiation to determinecharacteristics of the target tissue. In known methods, the amplitudesand wavelengths of the returned radiation are analyzed to determinecharacteristics of the target tissue. For instance, U.S. Pat. No.4,718,417 to Kittrell et al. discloses a method for diagnosing the typeof tissue within an artery, wherein a catheter is inserted into anartery and excitation light at particular wavelengths is used toilluminate the interior wall of the artery. Material or tissue withinthe artery wall emits fluorescent radiation in response to theexcitation light. A detector detects the fluorescent radiation andanalyzes the amplitudes and wavelengths of the emitted fluorescentradiation to determine whether the illuminated portion of the arterywall is normal, or covered with plaque. The contents of U.S. Pat. No.4,718,417 are hereby incorporated by reference.

[0005] U.S. Pat. No. 4,930,516 to Alfano et al. discloses a method fordetecting cancerous tissue, wherein a tissue sample is illuminated withexcitation light at a first wavelength, and fluorescent radiationemitted in response to the excitation light is detected. The wavelengthand amplitude of the emitted fluorescent radiation are then examined todetermine whether the tissue sample is cancerous or normal. Normaltissue will typically have amplitude peaks at certain known wavelengths,whereas cancerous tissue will have amplitude peaks at differentwavelengths. Alternatively the spectral amplitude of normal tissue willdiffer from cancerous tissue at the same wavelength. The disclosure ofU.S. Pat. No. 4,930,516 is hereby incorporated by reference.

[0006] Still other patents, such as U.S. Pat. No. 5,369,496 to Alfano etal., disclose methods for determining characteristics of biologicalmaterials, wherein a target tissue is illuminated with light, andbackscattered or reflected light is analyzed to determine the tissuecharacteristics. The contents of U.S. Pat. No. 5,369,496 are herebyincorporated by reference.

[0007] These methods rely on the information from steady state emissionsto perform a diagnostic measurement. It is known that the accuracy ofmeasurements made by these methods is limited by practical issues suchas variation in lamp intensity and changes in fluorophore concentration.It is desirable to measure an intrinsic physical property to eliminateerrors that can be caused by practical problems, to thereby make anabsolute measurement with greater accuracy. One intrinsic physicalproperty is the fluorescence lifetime or decay time of fluorophoresbeing interrogated, the same fluorophores that serve as indicators ofdisease in tissue.

[0008] It is known to look at the decay time of fluorescent emissions todetermine the type or condition of an illuminated tissue.

[0009] To date, apparatus for detection of the lifetime of fluorescentemissions have concentrated on directly measuring the lifetime of thefluorescent emissions. Typically, a very short burst of excitation lightis directed at a target tissue, and fluorescent emissions from thetarget tissue are then sensed with a detector. The amplitude of thefluorescent emissions are recorded, over time, as the fluorescentemissions decay. The fluorescent emissions may be sensed at specificwavelengths, or over a range of wavelengths. The amplitude decayprofile, as a function of time, is then examined to determine a propertyor condition of the target tissue.

[0010] For instance, U.S. Pat. No. 5,562,100 to Kittrell et al.discloses a method of determining tissue characteristics that includesilluminating a target tissue with a short pulse of excitation radiationat a particular wavelength, and detecting fluorescent radiation emittedby the target tissue in response to the excitation radiation. In thismethod, the amplitude of the emitted radiation is recorded, over time asthe emission decays. The amplitude profile is then used to determinecharacteristics of the target tissue. Similarly, U.S. Pat. No. 5,467,767to Alfano et al. also discloses a method or determining whether a tissuesample includes cancerous cells, wherein the amplitude decay profile offluorescent emissions are examined. The contents of U.S. Pat. Nos.5,562,100 and 5,467,767 are hereby incorporated by reference.

[0011] Unfortunately, these methods require expensive components thatare capable of generating extremely short bursts of excitation light,and that are capable of recording the relatively faint fluorescentemissions that occur over time. The high cost of these components hasprevented these techniques from being used in typical clinical settings.Other U.S. patents have explained that the decay time of fluorescentemissions can be indirectly measured utilizing phase shift or polaranisotropy measurements. For instance, U.S. Pat. No. 5,624,847 toLakowicz et al. discloses a method for determining the presence orconcentration of various substances using a phase shift method. U.S.Pat. No. 5,515,864 to Zuckerman discloses a method for measuring theconcentration of oxygen in blood utilizing a polar anisotropymeasurement technique. Each of these methods indirectly measure thelifetime of fluorescent emissions generated in response to excitationradiation. The contents of U.S. Pat. Nos. 5,624,847 and 5,515,864 arehereby incorporated by reference.

SUMMARY OF THE INVENTION

[0012] The invention encompasses apparatus and methods for determiningcharacteristics of target tissues within or at the surface of apatient's body, wherein excitation electromagnetic radiation is used toilluminate a target tissue and electromagnetic radiation returned fromthe target tissue is analyzed to determine the characteristics of thetarget tissue. Some apparatus and methods embodying the invention can beused to perform a diagnosis at or slightly below the surface of apatient=s tissues. For instance, methods and apparatus embodying theinvention could be used to diagnose the condition of a patient=s skin,the lining of natural body lumens such as the gastrointestinal tract, orthe surfaces of body organs or blood vessels. Embodiments of theinvention are particularly well suited to analyzing epithelial tissue.Other apparatus and methods embodying the invention can be used toperform a diagnosis deep within a patient=s body tissues where theexcitation radiation has to pass through several centimeters of tissuebefore it interacts with the target tissue, such as in diagnosis oftumors and lesions deep in a patient=s breast.

[0013] The returned electromagnetic radiation can comprise onlyfluorescent emissions from the target tissue that are caused by theexcitation electromagnetic radiation. In this instance, apparatus ormethods embodying the invention would measure the lifetime or decay timeof the fluorescent emissions and use this information to determinecharacteristics of the target tissue. The fluorescent emissions may begenerated by endogenous or exogenous fluorescent materials in the targettissue. Both phase shift and polar anisotropy techniques can be used toperform these types of measurements.

[0014] The returned electromagnetic radiation can also comprise aportion of the electromagnetic radiation that is scattered or reflectedfrom or transmitted through the target tissue. Analysis of thescattered, reflected or transmitted excitation radiation gives a measureof absorption and scattering characteristics of the target tissue. Thisinformation can be used by itself to provide a diagnosis, or theinformation can be used to calibrate the results of the fluorescentemission measurements to arrive at a more accurate measurement. Thereflected or scattered excitation radiation can be measured usingintensity based techniques, or phase shift techniques.

[0015] In phase shift techniques for measuring either reflected orscattered excitation radiation, or fluorescent emissions caused by theexcitation radiation, the excitation electromagnetic radiation isamplitude modulated at a predetermined frequency. A detector that sensesthe returned radiation (either reflected/scattered excitation radiationor fluorescent emissions) is used to detect the amplitude and timingcharacteristics of the returned electromagnetic radiation. Theexcitation and returned radiation will have the same frequency, but theamplitude of the returned radiation should be smaller than the amplitudeof the excitation radiation, and the returned radiation will be out ofphase with the excitation radiation. The demodulation and phase shiftbetween the excitation and returned electromagnetic radiation gives ameasure of the characteristics of the target tissue. The demodulationamount can be represented by a demodulation factor, which is a ratio ofthe AC and DC amplitude components of the excitation and returnedelectromagnetic radiation.

[0016] A polar anisotropy technique may also be used to detectfluorescent emissions to obtain a measure of the decay time or lifetimeof the fluorescent emissions. In the polar anisotropy techniques, thetarget tissue is illuminated with polarized excitation electromagneticradiation. The returned fluorescent emissions are conveyed to apolarizing beam splitter that separates the returned electromagneticradiation into two light beams that are polarized in mutuallyperpendicular planes. In a preferred embodiment, one plane is parallelto the polarization plane of the excitation radiation, and the secondplane is perpendicular to that plane. Detectors detect the amplitudes ofthe two perpendicularly polarized beams of light. The detectedamplitudes are used to calculate an anisotropy factor that isrepresentative of the lifetime or decay time of the fluorescentemissions.

[0017] In either the phase shift or polar anisotropy techniques, theapparatus or method may only analyze returned radiation within certainpredetermined wavelengths. Also, the apparatus and methods may onlyanalyze fluorescent decays that occur for more than a predeterminedperiod of time, or less than a predetermined period of time. This allowsthe device to distinguish between different types of tissues that havedifferent fluorescent decay times.

[0018] Because of changes in the fluorescent emissions of endogenous andexogenous fluorophores that occur within a patient=s body, theabove-described methods were not previously used for in vivo detectionof cancerous or diseased tissues. Methods and apparatus embodying thepresent invention, however, glow for in vivo detection of diseasedtissues using relatively simple and inexpensive instrumentation.

[0019] The above described techniques can be used to determine theconditions of multiple portions of a target tissue, and the determinedconditions can be used to create a map of the target tissue. Such a mapcould then be either displayed on a display screen, or presented in hardcopy format.

[0020] An instrument embodying present invention could be in the for ofan endoscope designed to be introduced into natural lumen or a cavity ofa patient=s body. Alternatively, the instrument might be in the form ofa catheter designed to be introduced into blood vessels of a patient=sbody. Regardless of whether the apparatus is in the form of an endoscopeor a catheter, the apparatus could include means for delivering atherapeutic pulse of electromagnetic radiation to the target tissue. Thedevice could also include means for delivering a therapeutic dose ofmedication to the target tissue. Further, the instrument could includemeans for sampling the target tissue depending upon the determinedcondition of the target tissue.

[0021] An apparatus embodying the invention that is well suited todeveloping a map of target tissue conditions may include a plurality ofoptical fibers that are arranged in a predetermined pattern on the faceof a test instrument. Each optical fiber would be capable of deliveringexcitation radiation and conducting return radiation to a detector.Alternatively, each detection position on the face of the instrumentcould include one optical fiber for delivering excitation radiation andanother fiber for receiving returned radiation. In yet otheralternatives, multiple fibers could be used at each position for theexcitation or return radiation, or both. By pressing the face of theinstrument against the target tissue, multiple measurements can be takenat multiple positions simultaneously.

[0022] An apparatus as described above could also be configured so thatonce a first set of measurements are taken with the instrument, thelocations of the optical fibers could be moved incrementally, and asecond set of measurements could be recorded. This could be done byrepositioning the instrument face, or by keeping the instrument facestationary, and repositioning the optical fibers behind the instrumentface. This process could be repeated several times to obtain multiplesets of readings from the target tissue. The additional sets ofmeasurements could be taken on the same area as the first set, or atdifferent locations on the target tissue.

[0023] An instrument as described above could be configured to allowrotation of the optical fibers between a plurality of predeterminedrotational positions. One embodiment could be configured so that theoptical fibers are located at a series of unique positions as theoptical fibers are rotated between the predetermined rotationalpositions. This would allow the device to capture multiple readings at alarge number of unique positions on the target tissue. Such a multiplecycle measurement process would allow greater resolution than would bepossible with a single measurement cycle.

[0024] Additional advantages, objects, and features of the inventionwill be set forth in part in the description which follows and in partwill become apparent to those having ordinary skill in the art uponexamination of the following or may be learned from practice of theinvention. The objects and advantages of the invention may be realizedand attained as particularly pointed out in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Preferred embodiments of the present invention will now bedescribed with reference to the following drawing figures, wherein likeelements are referred to with like reference numerals, and wherein:

[0026]FIG. 1 is a chart showing the amplitudes and phase shift ofexcitation and returned electromagnetic radiation;

[0027]FIG. 2 is a diagram showing an apparatus embodying the inventioncapable of performing a phase shift measurement;

[0028]FIG. 3 is a diagram showing an apparatus embodying of theinvention capable of performing a polar anisotropy measurement;

[0029]FIG. 4 is a diagram of an endoscope embodying the invention;

[0030]FIGS. 5A and 5B show an embodiment of the invention;

[0031]FIGS. 6A, 6B and 6C show the end portions of various embodimentsof the invention;

[0032]FIG. 7 shows the steps of a method embodying the invention;

[0033]FIG. 8 shows the steps of another method embodying the invention;

[0034]FIG. 9 is a cross-sectional view of a device embodying theinvention;

[0035]FIGS. 10A and 10B are cross sectional views of the device shown inFIG. 9 taken along section line 10-10;

[0036]FIG. 11 is a diagram showing the pattern of interrogation pointsof a device embodying the invention;

[0037]FIG. 12 is another diagram showing the pattern of interrogationpoints of a device embodying the invention;

[0038]FIG. 13 is yet another diagram showing the pattern ofinterrogation points of a device embodying the invention; and

[0039]FIG. 14 is a block diagram of a device embodying the invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0040] The phase shift and polar anisotropy techniques that can be usedin devices embodying the invention are more simple and less expensive toimplement than the known apparatus and techniques for detecting thelifetime or decay time of fluorescent emissions. As a result, they canbe implemented for real world in vivo testing of target tissues.

[0041] It is known that when a fluorophore is excited with aninfinitesimal pulse of light, the resulting fluorescent emission decaysexponentially. The intensity of the fluorescent emission is given byEquation (1), where I_(i) is the initial fluorescence intensity, t isthe time, and t is the fluorescence lifetime.

I(t)=I_(i)e^(−t/t)  Equation (1)

[0042] If an excitation light is amplitude modulated at a constantfrequency, instead of simply illuminating the target tissue with a shortburst of light, the resulting fluorescence emissions will also appear tobe amplitude modulated. The amplitude of the fluorescent emissions willbe smaller than the amplitude of the excitation light, but thefluorescent emissions will have the same frequency. Also, there will bea phase shift between the excitation light and the fluorescentemissions.

[0043]FIG. 1 illustrates the concept of illuminating a target tissuewith amplitude modulated excitation electromagnetic radiation andsensing the resulting fluorescent emissions. In FIG. 1, the waveform Xshows the amplitude of modulated excitation electromagnetic radiationfrom a source. The amplitude of returned fluorescent emissions is shownas waveform Y. As can be seen in FIG. 1, the peaks of the waveform Y aredelayed, or phase shifted, relative to the peaks of waveform X by anamount q. This is referred to as a phase shift amount.

[0044] In addition, the amplitude of the fluorescent emissions issmaller than the amplitude of the excitation light source. Ademodulation factor m represents a ratio of the DC and AC components ofthe fluorescent emissions relative to the DC and AC components of theexcitation electromagnetic radiation.

[0045] The Fourier transform of equation (1), yields Equation (2), shownbelow.

I(w)=I _(i) t/(1−iwt)  Equation (2)

[0046] Equation (2), in turn, can be used to derive the phase shirt anddemodulation factor, as shown in Equations (3) and (4) below.

q _(s)=tan⁻¹(wt)  Equation (3)

m=1/%(1+w ² t ²)  Equation (4)

[0047] An apparatus for in vivo determination of the characteristics ofa target tissue utilizing a phase shift technique will now be describedwith reference to FIGS. 1 and 2.

[0048] A diagram of an apparatus embodying the invention is shown inFIG. 2. The apparatus includes a source 20 of electromagnetic radiation,which is connected to a frequency synthesizer 46. The radiation source20 produces electromagnetic radiation that is conducted to a targettissue 50. The radiation may be conducted to the target tissue 50through one or more emission optical fibers 52. The apparatus maw alsoinclude a filter 22 for controlling the electromagnetic radiationemitted from the radiation source 20. The radiation source couldcomprise a laser, alight emitting diode, a fluorescent tube, anincandescent bulb, or any other type of device that is capable ofemitting electromagnetic radiation, as is well known to those skilled inthe art.

[0049] Electromagnetic radiation returned from target tissue 50, issensed by a detector 56. The returned electromagnetic radiation couldcomprise either a portion of the excitation electromagnetic radiationthat is scattered or reflected from the target tissue, or fluorescentemissions from fluorophores in the target tissue that have been excitedby the excitation radiation. The detector may comprise a photomultipliertube, a photosensitive diode a charge coupled device, or any other typeof electromagnetic radiation sensor, as is also well known to thoseskilled in the art.

[0050] If the detector is a small charge coupled device, it could belocated at a distal end of an endoscope or catheter instrument. In thisinstance, the charge coupled device would already be located adjacentthe target tissue such that the detector could directly sense the returnradiation. The charge coupled device would then need some means forcommunicating its information to a processor 44.

[0051] If the detector is not a charge coupled device located at adistal end of an instrument, the returned electromagnetic radiation maybe conducted to the detector 56 through one or more return opticalfibers 54. The return optical fibers 54 and the excitation opticalfibers 52 may be co-located within the same instrument, or they may belocated in separate instruments. Alternately, the same optical fiberswithin an instrument may be used to perform both excitation and returnfunctions.

[0052] The frequency synthesizer 46 is a combination of two highfrequency synthesizers that are preferably phase locked. The frequencysynthesizer outputs three signals. The first signal has a frequency F,the second signal has a frequency of F+f, which is a slightly infrequency than the signal F, and the third signal has a frequency f,which is lower in frequency than the first two signals. The excitationradiation from the radiation source 20, which illuminates the targettissue 50, is amplitude modulated at the high frequency F. The signalF+f drives the detector 56. Finally, the low frequency signal f, whichis readily derived as the difference between the two high frequencysignals, is sent as a reference signal to the processor 44.

[0053] The embodiment shown in FIG. 2, is a heterodyne system. Thedetector 56 senses the returned radiation and generates a signal that ismodulated at the same frequency as the excitation radiation, or thefrequency F. The detector 56 then uses the higher frequency signal F+fto convert the signal corresponding to the returned radiation into a lowdifference frequency signal f=, which includes information on thereturned radiation signal. The low frequency signal f= is then comparedto the low frequency signal f, which was generated by the frequencysynthesizer 46, to calculate a phase shift q and demodulation factor m.Other types of heterodyne systems could also be used.

[0054] The processor device 44 may include a memory 45 and a display 47.In fact, the processor device may comprise a typical personal computer.The processor 44 may also be configured to determine the AC and DCcomponents of the amplitudes of the excitation and returnedelectromagnetic radiation signals. The processor may also be configuredto calculate a demodulation factor m. As shown in FIG. 1, thedemodulation factor m represents a ratio of the AC component B dividedby the DC component A of the returned electromagnetic radiation to theAC component b divided by the DC component a of the excitationelectromagnetic radiation. The demodulation factor can be used inconjunction with the phase difference f to more accurately determinecharacteristics of the target tissue.

[0055] If the detector 56 is measuring scattered or reflectedelectromagnetic radiation, the phase difference and the demodulationfactor will provide information about the absorption and reflectioncharacteristics of the target tissue. If the detector 56 is measuringfluorescent radiation emitted by the target tissue, the phase differenceand the demodulation factor will provide information about the lifetimeand intensity of the fluorescent emissions. In either event, thisinformation can be helpful in determining characteristics of the targettissue. For instance, this information can be used to determine whethera tissue is cancerous or not, the information can be used to distinguishbetween different types of tissue, and the information can be used todetermine chemical properties or the concentrations of various chemicalsor ions present in the target tissue.

[0056] If the apparatus described above is used to detect fluorescentemissions, the fluorescent emissions can be generated by endogenous orexogenous fluorophores. If the fluorescent material is exogenous, thematerial may be selected so that it chemically interacts with variouscompounds in the patient=s body. In this instance, the fluorescentlifetime of the exogenous material would vary depending upon thepresence or concentration of a compound or ion. As a result, the phasedifference value, and/or the demodulation factor m can be used todetermine the presence or concentration of the compound or ion. Examplesof exogenous fluorescent materials that would be useful in a method asdescribed above are set forth in U.S. Pat. No. 5,624,847 and U.S. Pat.No. 5,628,310, the contents of each of which are hereby incorporated byreference.

[0057] A second apparatus and method embodying the invention, whichmeasures fluorescent lifetime via a polarization anisotropy measurementtechnique, will now be described with reference to FIG. 3. In thismeasurement technique, a polarized beam of electromagnetic radiation isused to illuminate a target tissue. Components of thefluorophores=excitation dipoles, parallel to the polarization plane ofthe beam of excitation electromagnetic radiation will then beselectively excited and will emit polarized fluorescent radiation. Thisemission will have a lifetime that is governed by the physiochemicalenvironment of the fluorophore. Because of Brownian motion, thefluorophores will rotate as they emit radiation. This rotation resultsin a change in the intensity in each of the emission polarizationplanes. Brownian rotation in essence provides a time gated window inwhich to observe the intensity decay due to fluorescence lifetime. Bymeasuring amplitudes of the emitted fluorescent radiation in mutuallyperpendicular planes, it is possible to determine the lifetime, or decaytime, of the fluorescent emissions. This measurement is possible only ifthe time constant of Brownian rotation, or the rotational correlationtime, is not vastly different from the fluorescence lifetime. For mostendogenous fluorophores that are indicators of disease this is true.Additionally, exogenous fluorophores can be engineered to satisfy thisrequirement for applications in disease detection. In a preferredembodiment of the invention, one polarization plane is parallel to thepolarization plane of the excitation radiation, and the other isperpendicular to that plane. This measuring method makes use of thePerrin Equation, which appears below as Equation (6). The PerrinEquation relates fluorescence anisotropy r to the fluorescent lifetime,where r₀ is the anisotropy of a molecule in the absence of Brownianmotion (the frozen or highly viscous state) and is the rotational(Brownian) correlation time.

r ₀ /r=1+t/f  Equation (6)

[0058] Strictly speaking, Equation (6) is only valid for a singleexponential decay of both fluorescence lifetime and anisotropy. Singleexponential anisotropy decay only occurs for a spherical molecule. Also,for simplicity, the rotational correlation time for a sphere is definedaccording to Equation (7) below, where h is the viscosity, V the volume,R the universal gas constant, and T the absolute temperature.

f=(hV)/(R,T)  Equation (7)

[0059] Using the above equations and assumptions, it is possible todefine the anisotropy factor r according to Equation (8), where I_(l) isthe intensity of fluorescent emissions in a plane parallel to the planeof the excitation electromagnetic radiation, and I_(r) is the intensityof fluorescent emissions in a plane perpendicular to the plane of theexcitation electromagnetic radiation.

r=(I _(l) −I _(r))/(I _(l)+2I _(r))  Equation (8)

[0060] An embodiment of the present invention which can measurefluorescent lifetimes, in vivo, by a polarization anisotropy techniquewill now be described with reference to FIG. 3. In FIG. 3, a source ofelectromagnetic radiation 20 emits excitation radiation which thenpasses through a polarizer 24, focusing optics 25, and optionally anemission filter 26. The radiation source 20 can be a laser, a lightemitting diode, a fluorescent light tube, an incandescent light bulb, orany other type of light emitting device. In an alternate embodiment, theradiation source 20 and the polarizer 24 could be replaced by aradiation source that emits polarized light.

[0061] The polarized and filtered excitation radiation then passesthrough a dichroic mirror 28, additional focusing optics 30, and one ormore optical fibers 31. The polarized excitation radiation exits theoptical fibers 31 and illuminates a target tissue 50. Fluorophores inthe target tissue 50 will emir fluorescent radiation in response to theexcitation electromagnetic radiation. The returned electromagneticradiation travels back up the optical fiber 31 and through the focusingoptics 30. Thee optical fibers 31 comprise polarization preservingoptical fibers such that the polarization of the excitation and returnradiation is preserved as the radiation transits the fiber. In otherembodiments, one or more emission optical fibers may be used tocommunicate the excitation radiation to the target tissue 50, and asecond group of return optical fibers may be used to communicate thereturn radiation back to the dichroic mirror 28.

[0062] The returned radiation is then reflected by the dichroic mirror28 through additional optics 29 and, optionally, another filter 32. Thereturned radiation then enters a polarizing beam splitter 34, whichseparates the returned electromagnetic radiation into two light beamsthat are polarized into mutually perpendicular planes. In a preferredembodiment, one polarization plane will be parallel to the polarizationplane of the excitation radiation, and the other polarization plane willbe perpendicular to that plane. A first one of the separated light beamshaving a first polarization plane illuminates a first detector 40A. Asecond of the separated light beams having a second polarization planethat is perpendicular to the first polarization plane illuminates asecond detector 40B. The first and second detectors 40A and 40B outputsignals indicative of the amplitudes of the first and second lightbeams. The signals from the first and second detectors are thenforwarded co a processor 44. The signals from the first and seconddetectors are used to calculate an anisotropy factor, which provides ameasure of the lifetime of the fluorescent emissions. As describedabove, the fluorescent lifetime can be used to determine variouscharacteristics of the target tissue.

[0063] A device or method embodying the present invention, utilizingeither the phase shift or the polar anisotropy techniques make itpossible to conduct in vivo measurements of tissues on the inside ofbody passages or lumens. An endoscope embodying the invention can beinserted into a natural body lumen of a patient to search for thepresence of cancerous or diseased tissue. This means that no surgerywould be required to locate and examine tissues inside the patient=sbody.

[0064] Either the phase shift or the polar anisotropy method may be usedto diagnose disease on the inside surfaces of a body lumen or tissueslocated immediately below the surface. Since the anisotropy detectionmethod relies on polarized light, a reliable measurement of fluorescencelifetime can be made to a depth of several millimeters before losingresolution due to the depolarizing nature of tissue scattering.

[0065] Additionally, the phase shift technique is capable of conductingdeep tissue measurements of tissues located several centimeters belowthe surface of a lumen or organ. This diagnosis is possible by eitherobserving the returned scattered excitation radiation or by observingthe scattered fluorescence radiation generated by tissue uponinteraction with the scattered excitation radiation. Thus, a deviceembodying the invention that uses the phase shift technique candetermine the presence of cancerous or diseased tissue located below orbehind the surface of the body lumen or deep within tissue such as inbreast or brain tissue.

[0066] The above-described methods could be combined to obtain a betteror more accurate measure of target tissue characteristics. For instance,a measurement of the phase shift and demodulation factor ofreflected/scattered excitation radiation and a measurement of the phaseshift and demodulation factor of a fluorescent emission could be usedtogether to obtain a more accurate determination of target tissuecharacteristics than one measurement alone. A phase shift anddemodulation measurement could also be combined with a polar anisotropymeasurement.

[0067] Similarly, the phase shift and polar anisotropy techniques couldbe used in conjunction with known intensity based measurementtechniques, as described above in the Background of The Invention, toobtain a better determination of target tissue characteristics.

[0068] Examples of methods that combine two or more measurementtechniques to arrive at a more accurate ultimate determination are givenin U.S. Pat. No. 5,582,168 to Samuels, the contents of which are herebyincorporated by reference.

[0069] The techniques described above could also be used to map theconditions of an area of target tissue. For instance, any of theabove-described techniques could be used to determine a condition of atarget tissue adjacent a distal end of a measuring device. The measuringdevice could then be moved adjacent a different portion of the targettissue, and the measurements could be repeated. This process could berepeated numerous times to determine the conditions of differentportions of a target tissue area. The determined conditions could thenbe used to create a map of the target tissue area, which could beprinted or displayed on a monitor.

[0070] One of the most difficult problems with in vivo tissuediagnostics and disease measurement is the biological diversity ofnormal tissue properties between different patients, or even within thesame patient. Furthermore, this diversity is variant both in the longterm and in the short term. Long term variations may be due to patientage, hormonal milieu, metabolism, mucosal viscosity, and circulatory andnervous system differences. Short term variations may be from bloodperfusion changes due to heart beat, physical movement, localtemperature changes etc.

[0071] Because of the variability of tissue characteristics, toaccurately determine whether a target tissue is diseased, one needs tocompare measurements of the target tissue to measurements of normaltissues from the same patient. The measurements of the known normaltissue should be made concurrently or simultaneously with themeasurements of the target tissue. The normal tissue measurements thenserve as a baseline for normalcy, variations from which may beinterpreted as disease. To arrive at a baseline measurement, a number ofstrategies can be used.

[0072] First, visual characteristics such as pigmentations (nevi) inskin, or polyps in the colon, can be used to identify potentiallyabnormal regions. Normalized or averaged spectra of multiple regionssurrounding these potentially abnormal, visually distinct regions can beused to establish baseline measurements. The baseline measurements canthen be compared to measurements taken on the abnormal, visuallydistinct regions. Measurements of normal and abnormal regions based onvisual characteristics could be automated using imaging capabilities ofthe measurement device itself.

[0073] In an alternate strategy, measurements can be taken on spacedapart regions along a portion of a lumen or tissue. The spacing betweenthe regions would be dependent on the type of tissue being diagnosed.Then, differentials between individual measurements taken at differentregions would be calculated. If differentials are greater than a presetamount, the tissue between the excessively high differentials would bediagnosed as diseased.

[0074] In yet another alternate strategy, a gradient in spectralresponse as one moves away from a visually suspicious site could also beused as a marker for disease. This is easily automated and can beimplemented effectively in any imaging modality.

[0075] In addition, pattern recognition algorithms (e.g. neural nets)could also be used to analyze differences in readings taken from varioussites in the same patient or from multiple readings from differentpatients.

[0076]FIG. 4 shows an endoscope that could be used to practice any ofthe above-described measuring techniques. The endoscope 60 includes atransmit optical fiber bundle 52, which can convey excitationelectromagnetic radiation from a radiation source 20 to a target tissue.The endoscope 60 also includes a return optical fiber bundle 54 forcommunicating reflected/scattered electromagnetic radiation orfluorescent emissions from a target tissue to a detector 56. Inalternative embodiments, the transmit and return optical fibers could beco-located, or could be the same fibers.

[0077] The endoscope 60 may also include a handle 62 for positioning theendoscope, or for operating a device 64 on a distal end of the endoscope60 intended to remove tissue samples from a patient. The endoscope mayalso include a device 66 for introducing a dose of medication to atarget tissue. Also, the source of electromagnetic radiation 20 may beconfigured to emit a burst of therapeutic radiation that could bedelivered to a target tissue by the endoscope.

[0078]FIGS. 5A and 5B show the structure of an endoscope or catheterwhich may embody the present invention. The apparatus includes a longbody portion 70 which is intended to be inserted into a body of thepatient. In the case of a catheter, the body portion 70 must have adiameter sufficiently small to be inserted into blood vessels of thepatient. In the case of an endoscope, the body portion of the device 70must have a diameter that is sufficiently small to be inserted into anatural lumen or body cavity of the patient.

[0079] The device includes a proximal end 80, which holds proximal endsof optical fibers 72 a-72 c. The optical fibers extend down the lengthof the device and terminate at a distal holding portion 74. The distalholding portion 74 holds the optical fibers in a predeterminedorientation. The optical fibers are held such that they can illuminateselected portions of the distal end 76 of the device. This orientationalso allows the distal end or the optical fibers to receive radiationfrom selected areas outside the distal end 76 of the device.

[0080] As best seen in FIG. 5B, the optical fibers are arranged suchthat there is a single central optical fiber 72 a surrounded by a firstring of optical fibers 72B, which is in turn surrounded by a second ringof optical fibers 72 c. Of course, other orientations of the opticalfibers are possible.

[0081] By applying excitation electromagnetic radiation to selected onesof the optical fibers, and monitoring the returned electromagneticradiation through selected ones of the optical fibers, is possible todetermine characteristics of target tissues at selected locationsoutside the distal end of the device. For instance, if the centraloptical fiber 72 a emits electromagnetic radiation 90 toward a targettissue, and returned electromagnetic radiation is sensed through thesame optical fiber, the returned electromagnetic radiation can beanalyzed using any of the above methods to determine characteristics ofa target tissue located adjacent the center of the distal end of thedevice. The same process can be used to determine the condition of atarget tissue at different locations around the distal end of thedevice.

[0082] FIGS. 6A-6C show various different distal ends of the device.

[0083] In FIG. 6A, the distal ends of the optical fibers are held by aholding portion 98 that aims the distal ends of the optical fibers 97 ina particular direction. A flexible wire or bar 96 is attached to theholding portion 98 and extends to the proximal end of the device. Byrotating the flexible wire or bar 96, the holding portion 98 can also berotated. This allows the distal ends of the optical fibers to be aimedat different portions of the distal end of the device.

[0084]FIG. 6B shows another embodiment of the invention that includesone or inflatable balloon portions 92 a., 92 b. An optical fiber 72 islocated in the center of the device by a holding portion 94. Each of theinflatable balloons 92 a, 92 b is also held by the holding portion 94.By selectively inflating or deflating the different balloon portions,the optical fiber 72 may be aimed to illuminate different portions ofthe distal end of the device or to receive return radiation fromselected locations adjacent the distal end of the device.

[0085]FIG. 6C shows an embodiment of the device similar to theembodiment shown in FIGS. 5A and 5B. This figure shows howelectromagnetic radiation passing down through the optical fibers 72a-72 c can be used to selectively illuminate material or tissue adjacentselected portions of the distal end of the device. In FIG. 6C, only theupper optical fibers are emitting electromagnetic radiation outside thedevice. This electromagnetic radiation is being used to destroy oratomize plaque which has formed on an inner wall of a blood vessel. Byapplying electromagnetic radiation to selected ones of the opticalfibers, a doctor can carefully remove or correct problems with targettissues or materials.

[0086]FIG. 7 shows steps of a method embodying the invention that can beused to determine the characteristics of a tissue adjacent a deviceembodying invention. In a first step S600, a target tissue isilluminated with amplitude modulated excitation electromagneticradiation. In second step S610, returned electromagnetic radiation isdetected with a detector. In step S620, a phase shift between theexcitation and return electromagnetic radiation is calculated. Inanother step S630, a demodulation factor representing a ratio of theamplitudes of the excitation and return electromagnetic radiation iscalculated. Step S630 is optional but may increase the accuracy of theresults. In a final step S640, characteristics of the target tissue aredetermined based on the calculated phase shift, and optionally thecalculated demodulation factor.

[0087]FIG. 8 shows another method embodying invention that can be usedto determine tissue characteristics. In the first step S710, the targettissue is illuminated with polarized electromagnetic radiation. In thenext step S720, the intensity of returned electromagnetic radiation isdetected in mutually perpendicular polarization planes. En a preferredembodiment, the amplitude would be detected in planes that are paralleland perpendicular to the polarization plane of the excitation radiation.In the next step S730, an anisotropy factor is calculated based on thedetected intensity values for the different polarization planes. In thefinal step S740, characteristics of a target tissue are determined basedon the calculated anisotropy factor.

[0088] Another device embodying the invention that can be used todetermine tissue characteristics is shown, in longitudinalcross-section, in FIG. 9. The instrument 110 includes a cylindricalouter housing 112 with a circular end cap 120 configured to abut thetarget tissue. A rotating cylindrical inner core 114 is mounted in theouter housing 112. A bundle of optical fibers 116 are located inside theinner core 114.

[0089] The optical fibers 116 pass down the length of the inner core 114and are arranged in a specific pattern at the end adjacent the end cap120 of the outer housing 112. The end of the inner core 114 adjacent theend cap 120 is mounted within the outer housing 112 with a rotatingbearing 122. The end cap 120 is at least partially transparent ortransmissive so that electromagnetic radiation can pass from the opticalfibers, through the end cap, to illuminate a target tissue adjacent theend cap 120. Light scattered from or generated by the target tissuewould then pass back through the end cap 120 and back down the opticalfibers 116.

[0090] The inner core 114 is also mounted inside the outer housing 112by a detent mechanism 118. The detent mechanism is intended to supportthe inner core 114, and ensure that the inner core is rotatable withinthe outer housing 112 by predetermined annular amounts.

[0091] A cross sectional view of a first embodiment of the instrument,taken along section line 10-10 of FIG. 9, is shown in FIG. 10A. Theinner core 114 is supported within the outer housing 112 by the detentmechanism. In this embodiment, the detent mechanism includes two mounts134 with spring loaded fingers 136 that are biased away from the innercore 114. The detent mechanism also includes four stoppers 130, each ofwhich has a central depression 132. The spring loaded fingers 136 areconfigured to engage the central depressions 132 of the stoppers 130 tocause the rotatable inner core to come to rest at predetermined angularrotational positions. In the embodiment shown in FIG. 10A, four stoppersare provided in the inner surface of the outer housing 112. Thus, theinner core 114 will be rotatable in increments of 90°. In alternateembodiments similar to the one shown in FIG. 10A, four mounts 134, eachhaving its own spring loaded finger 136, could be attached to the innercore 114. The provision of four such mounts would serve to keep theinner core 114 better centered inside the outer housing 112.

[0092] An alternate embodiment of the detent mechanism is shown in FIG.10B. In this embodiment, six stoppers 130 are spaced around the insideof the outer housing 112. Three mounts 134, each having its own springloaded finger 136, are mounted on the inner core 114. The three mounts134 are spaced around the exterior of the inner core 114 approximately120° apart. This embodiment will allow the inner core to be rotated topredetermined positions in increments of 60°. La addition, the locationof the three mounts. 120° apart, helps to keep the inner core 114supported in the center of the outer housing 112.

[0093] The ends of the optical fibers may be mounted on a circular endplate 121 that holds the optical fibers in a predetermined pattern. Thecircular end plate 121 would be rigidly attached to the end of thecylindrical inner core 114. In addition, an index matching agent 123 maybe located between the end plate 121 and the end cap 120 on the outerhousing 112. The index matching agent 123 can serve as both an opticalindex matching agent, and as a lubricant to allow free rotation of theend plate 121 relative to the end cap 120.

[0094] A diagram showing how the optical fibers are positioned on theface of an embodiment of the instrument is shown in FIG. 11. The face ofthe instrument, which would be the end cap 120 of the device shown inFIG. 9, is indicated by reference number 140 in FIG. 11. The blackcircles 142 represent the locations of optical fibers behind the end cap120. The hollow circles 144 represent the positions that the opticalfibers will move to if the inner core 114 of the instrument is rotated90°. Thus, each of the circles represent positions that can beinterrogated with the optical fibers.

[0095] In some embodiments of the device, a single optical fiber will belocated at each of the positions shown by the black circles 142 in FIG.11. In this instance, excitation light would travel down the fiber andbe emitted at each interrogation position indicated by a black circle142. Light scattered from or produced by the target tissue would travelback up the same fibers to a detector or detector array. In alternateembodiments, pairs of optical fibers could be located at each positionindicated by a black circle 142. In the alternate embodiments, oneoptical fiber of each pair would conduct excitation light to the targettissue, and the second optical fiber of each pair would conduct lightscattered from or generated by the target tissue to a detector. In stillother alternate embodiments, multiple fibers for carrying excitationlight and/or multiple fibers for carrying light scattered from orgenerated by the target tissue could be located at each interrogationposition indicated by a black circle 142.

[0096] To use an instrument having the optical fiber pattern shown inFIG. 11, the instrument would first be positioned so that the end cap120 is adjacent the target tissue. The end cap 120 may be in contactwith the target tissue, or it might be spaced from the surface of thetarget tissue. Also, an index matching material may be interposedbetween the end cap and that target tissue. Then, the optical fiberswould be used during a first measurement cycle to simultaneously measuretissue characteristics at each of the interrogation positions in FIG. 11having a black circle 142. The tissue characteristics could be measuredusing any of the measurement techniques discussed above. Then, the innercore 114 would be rotated 90° within the outer housing 112, and theoptical fibers would be used during a second measurement cycle tosimultaneously measure tissue characteristics at each of theinterrogation positions in FIG. 11 having a hollow circle 144.

[0097] Constructing an instrument as shown in FIGS. 9, 10A or 10B, andhaving the optical fiber pattern shown in FIG. 11, has several importantadvantages. First, constructing an instrument in this manner allows theinstrument to interrogate many more points in the target tissue thanwould have been possible if the inner core did not rotate. The abilityto rotate the inner core 114, and take a second series of measurementsat different locations on the target tissue, essentially increases theresolution of the device.

[0098] In addition, when a large number of optical fibers are packedinto the tissue contacting face of an instrument, cross-talk between theoptical fibers can occur. The cross-talk can occur when excitation lightfrom one interrogation position scatters from the target tissue andenters an adjacent interrogation position. Cross-talk can also occur ifexcitation light from a first interrogation position travels through thetarget tissue and enters an adjacent interrogation position. One of theeasiest ways to reduce or eliminate cross-talk is to space theinterrogation positions farther apart. However, increasing the spacingbetween interrogation positions will reduce the resolution of thedevice.

[0099] An instrument embodying the present invention, with a rotatableinner core, allows the interrogation positions to be spaced far enoughapart to reduce or substantially eliminate cross-talk, while stillobtaining excellent resolution. Thus, good resolution is obtainedwithout the negative impact to sensitivity or selectivity caused bycross-talk. In addition, fewer optical fibers and fewer correspondingdetectors are required to obtain a given resolution.

[0100] In addition, the ability to obtain a plurality of tissuemeasurements simultaneously from positions spaced across the entiretarget tissue has other benefits. If the instrument is intended todetect cancerous growths or other tissue maladies, the target tissuearea interrogated by the instrument is likely to have both normaltissue, and diseased tissue. As noted above, tissue characteristics canvary significantly from person to person, and the tissue characteristicscan vary significantly over relatively short periods of time. For thesereasons, the most effective way to determine the locations of diseasedareas is to establish a baseline for normal tissue, then compare themeasurement results for each interrogation point to the baselinemeasurement. In other words, the easiest way to determine the locationof a diseased area is to simply look for a measurement aberration orvariance.

[0101] Because tissue characteristics can change relatively quickly, inorder to establish accurate, clearly defined variances between tissuecharacteristics, it is desirable to take a plurality of readingssimultaneously over as large an area as possible. Ideally, allmeasurements should be conducted during the same time period. Becausetissue tumors can be as small as approximately 1 mm, the resolution ofthe device is preferably 1 mm. In other words, to obtain the requisiteresolution, the spacing between interrogation positions should be 1 mm.Unfortunately, when the interrogation positions are 1 mm apart,significant cross-talk can occur, and the accuracy of the measurementresults is poor.

[0102] An instrument embodying the present invention allows theinterrogation positions to be spaced sufficiently far apart toessentially eliminate crosswalk, while still obtaining the requisite 1mm resolution. Although not all measurements are obtained at exactly thesame time, during each measurement cycle, simultaneous measurements aremade at positions spaced across the entire target tissue, which shouldinclude both normal and diseased areas. Thus, the results from eachmeasurement cycle can be used to detect variances in tissuecharacteristics that help to localize diseased areas. For these reasons,an instrument embodying the present invention balances the competingdesign requirements or resolution, elimination of cross-talk, and thedesire to make all measurements simultaneously to ensure thattime-varying tissue characteristics are taken into account.

[0103] A second arrangement for the optical fibers of a device as shownin FIG. 9 is depicted in FIG. 12. In this embodiment, the interrogationpositions are arranged in a hexagonal honeycomb pattern. The blackcircles 142 indicate the positions that would be occupied by opticalfibers during a first measurement cycle, and the hollow circles 144indicate positions that would be occupied by the optical fibers during asecond measurement cycle after the inner core 112 has been rotated by60°. This pattern achieves maximum spacing between adjacentinterrogation positions during each measurement cycle, and essentiallydoubles the resolution of the instrument.

[0104] A third arrangement for the optical fibers of a device shown inFIG. 9 is depicted in FIG. 13. In this embodiment, the optical fibersare again arranged according to a hexagonal honeycomb pattern. However,far fewer optical fibers are used in this embodiment. This thirdembodiment is intended for use in a measurement process that calls forsix measurement cycles. The inner core of the device would be rotated60° between each measurement cycle. Over the course of the sixmeasurement cycles, the device would ultimately interrogate all theblack circled 142 and hollow circled 144 interrogation positions shownin FIG. 13. This embodiment allows for even greater separation distancesbetween interrogation positions (to reduce or substantially eliminatecross-talk) while still achieving excellent measurement resolution. Inaddition, far fewer optical fibers and corresponding detectors would berequired to achieve a given measurement resolution.

[0105] Experimental studies were conducted by the applicants todetermine the spacing between interrogation positions that is needed tosubstantially eliminate cross-talk. The studies were conducted using apair of optical fibers at each interrogation position, wherein one fiberin each pair provides excitation light, and the other fiber in each pairis used to detect light. The excitation optical fibers had a diameter of200 mm, and the detection fibers had a diameter of 100 mm. Measurementswere made on optical reference standards, and tissue. Under theseconditions, it was necessary to space the interrogation positionsapproximately 3 mm apart to substantially eliminate cross-talk. Thus, ifan instrument were not designed as described above, so that the innercore can rotate the interrogation positions to different locations onthe target tissue, the device would only be capable of achieving aresolution of 3 mm.

[0106] The presently preferred embodiment of the invention utilizes anoptical fiber pattern similar to the one shown in FIG. 13. Thus, thedevice is designed to conduct six measurement cycles to complete allmeasurements within the target tissue. The inner core 114 is rotated 60°between each measurement cycle. The presently preferred embodimentutilizes optical fiber pairs at each interrogation position. Eachoptical fiber pair includes an excitation fiber having a 200 mmdiameter, and a detection optical fiber having a 100 mm diameter. Thearrangement of the optical fibers allows the interrogation positions tobe spaced approximately 3.0-3.5 mm apart, while still achieving aresolution of approximately 1 mm.

[0107] To determined the locations of diseased areas within a targettissue it is necessary to take measurements at a plurality of differentlocations in the target tissue spaced in at least two dimensions. Eachmeasurement may require multiple excitation wavelengths, and detectionof multiple wavelengths of scattered or generated light. Thus, themeasurements involve three measurement dimensions, two dimensions forthe area of the target tissue, and a third dimension comprising thespectral information. A device capable of conducting measurements inthese three dimensions is shown in FIG. 14.

[0108] The instrument includes a light source 20, and a filter assembly22. A plurality of excitation optical fibers 116 a lead from the filterassembly 22 to the target tissue 50. A plurality of detection fibers 116b lead away from the target tissue 50. The excitation optical fibers 116a and the detection optical fibers 116 b are arranged in pairs asdescribed above.

[0109] The light source 20 and filter assembly 22 allow specificwavelengths of light to be used to illuminate the target tissue 50 viathe excitation optical fibers 116 a. The filter assembly 22 could be asingle band pass optical filter, or multiple optical filters that can beselectively placed between the light source 20 and the excitationoptical fibers 116 a. Alternatively, the light source 20 and filterassembly 22 could be replaced with a wavelength tunable light source. Inyet other alternate embodiments, a plurality of light sources, such aslasers, could be used to selectively output specific wavelengths orwavelength bands of excitation light.

[0110] The detection fibers lead to an optical system 55. The light fromthe detection fibers 116 b passes through the optical system and into adetector array 56. The detector array may comprise a plurality ofphotosensitive detectors, or a plurality of spectrophotometers. Thedetector array 56 is preferably able to obtain measurement results foreach of the detection fibers 116 b simultaneously.

[0111] The optical system 55 can include a plurality of optical filtersthat allow the detector array to determine the intensity of light atcertain predetermined wavelengths. In a preferred embodiment, thedetector array would be a two dimensional array of photosensitivedetectors, such as a charge coupled device (CCD). The optical systemwould comprise a spectrograph that is configured to separate the lightfrom each detection optical fiber 116 b into a plurality of differentwavelengths, and to focus the different wavelengths across a line ofpixels on the CCD. Thus, each line of pixels on the CCD would correspondto a single detection fiber. The intensities of the differentwavelengths of light carried by a single detection fiber 116 b could bedetermined based on the outputs of a line pixels of the CCD. The greaterthe output of a particular pixel, the greater the intensity at aparticular wavelength.

[0112] The preferred embodiment is able to achieve excellentflexibility. Because all wavelengths of light are always detected, theinstrument software can simply select the pixels of interest for eachmeasurement, and thereby determine the intensity at particularwavelengths. During a first measurement, certain pixels representativeof scattering characteristics could be examined. During a subsequentmeasurement, different pixels representative of fluorescentcharacteristics could be examined. Also, the device could be essentiallyreconfigured to take completely different measurements by simplychanging the control software. Thus, a single device could be used for awide variety of different kinds of measurements.

[0113] In preferred methods of the present invention, one of thestructures described above would be used to conduct a series ofmeasurements cycles, and the inner core of the device would be rotatedbetween measurement cycles. In the preferred methods, however, two ormore measurements may be conducted during each measurement cycle. Forinstance, during a single measurement cycle the device may conduct ameasurement of scattering characteristics, and a measurement offluorescent characteristics. Once all measurement of a measurement cycleare completed, the inner core would be rotated, and additionalmeasurement cycles would be conducted.

[0114] In each of the embodiments described immediately above, aplurality of measurement cycles are conducted on a target tissue, and aninner core having optical fibers arranged in a predetermined pattern isrotated between measurement cycles. Although the presently preferredembodiments utilize rotating devices to accomplish a plurality ofmeasurements on a target tissue, alternate embodiments could use someother movement mechanism other than a rotating one. The inventionencompasses other types of movement or translational devices that allowa plurality of measurements to be taker on a target tissue with alimited number of detectors that are spaced far enough apart to avoidcross-talk.

[0115] The foregoing embodiments are merely exemplary and are not to beconstrued as limiting the present invention. The present teaching can bereadily applied to other types of apparatuses. The description of thepresent invention is intended to be illustrative, and nor to limit thescope of the claims. Many alternatives, modifications, and variationswill be apparent to those skilled in the art.

What is claimed is:
 1. An instrument for determining characteristics ofa target material comprising: an outer housing; an inner core that isrotatably mounted within the outer housing; a plurality of interrogationdevices mounted on the inner core in a predetermined pattern; and adetent mechanism attached to the inner core, wherein the detentmechanism is configured to allow the inner core to be rotated between aplurality of predetermined rotational positions relative to the outerhousing.
 2. The instrument of claim 1, wherein the plurality ofinterrogation devices are mounted on the inner core so that when theinner core is positioned at a first predetermined rotational position,the interrogation devices are positioned adjacent a first pluralityinterrogation positions relative to the outer housing, and whereinrotation of the inner core from the first predetermined rotationalposition to a second predetermined rotational position causes theplurality of interrogation devices to be repositioned adjacent a secondplurality of interrogation positions.
 3. The instrument of claim 2,wherein the instrument is configured such that the plurality ofinterrogation devices are repositioned to a plurality of predeterminedinterrogation positions each time the inner core is rotated to acorresponding predetermined rotational position.
 4. The instrument ofclaim 3, wherein none of the predetermined interrogation positions arecoincident.
 5. The instrument of claim 1, wherein the predeterminedpattern in which the plurality of interrogation devices are mounted onthe inner core minimizes cross-talk between adjacent interrogationdevices.
 6. The instrument of claim 1, wherein sensing portions of theplurality of interrogation devices are mounted on a face of the innercore, and wherein the predetermined pattern in which the plurality ofinterrogation devices are mounted on the inner core distributes theplurality of interrogation devices substantially evenly across the faceof the inner core.
 7. The instrument of claim 1, wherein the pluralityof interrogation devices comprise a plurality of optical fibers.
 8. Theinstrument of claim 7, wherein at least two optical fibers are locatedat each interrogation position, wherein at least one optical fiber ateach interrogation position is configured to conduct excitation light tothe interrogation position, and wherein at least one optical fiber ateach interrogation position is configured to receive light that isscattered from or generated by a target material.
 9. The instrument ofclaim 7, further comprising a detector array, wherein light scatteredfrom or generated by a target material is conducted to the detectorarray by at least some of the optical fibers.
 10. The instrument ofclaim 1, wherein stops are formed on an inner surface of the outerhousing, and wherein the detent mechanism comprises at least one detentmount that is attached to the inner core and that is configured tointeract with the stops to hold the inner core in the plurality ofpredetermined rotational positions.
 11. The instrument of claim 10,wherein each stop includes a depression, wherein each at least onedetent mount includes a biased member, and wherein each biased member isconfigured to nest in a depression of a stop to hold the inner core inone of the plurality of predetermined rotational positions.
 12. Theinstrument of claim 1, wherein the detent mechanism is configured tosupport at least a portion of the inner core inside the outer housing.13. The instrument of claim 1, wherein the outer housing includes an endcap, and wherein the plurality of interrogation devices are configuredto project excitation light through the end cap and to detect light froma target material that passes through the end cap.
 14. The instrument ofclaim 13, wherein an index matching agent is located between the end capand the plurality of interrogation devices.
 15. The instrument of claim14, wherein the index matching agent also acts as a lubricant to allowthe inner core to rotate freely within the outer housing.
 16. Aninstrument for determining characteristics of a target material,comprising: an outer housing; means for determining characteristics of atarget material at a plurality of predetermined interrogation locationsarranged in a predetermined pattern; and means for holding thedetermining means in a plurality of predetermined positions relative tothe outer housing.
 17. The instrument of claim 16, wherein the device isconfigured such that moving the determining means between the pluralityof predetermined positions allows the determining means to determinecharacteristics of a target material at a plurality of interrogationslocations, and wherein none of the interrogation locations arecoincident.
 18. The instrument of claim 16, wherein the predeterminedpattern minimizes cross-talk between adjacent interrogation locations.19. The instrument of claim 16, wherein the outer housing includes anend cap, and wherein the interrogation locations are substantiallyevenly distributed across the end cap.
 20. A method of detectingcharacteristics of a target material, comprising the steps of:positioning a plurality of interrogation devices that are arranged in apattern adjacent a first plurality of interrogation positions on atarget material; detecting characteristics of the target material at thefirst plurality of interrogation positions; repositioning the pluralityof interrogation devices so that they are adjacent at least oneadditional plurality of interrogation positions on the target material,wherein the first and at least one additional plurality of positions arenot coincident; and detecting characteristics of the target material atthe at least one additional plurality of interrogation positions. 21.The method of claim 20, wherein the repositioning step comprisesrotating the plurality of interrogation devices around a common axis.22. The method of claim 20, wherein each detecting step comprises thesteps of: detecting a first type of characteristics of the targetmaterial at a plurality of interrogation positions; and detecting asecond type of characteristics of the target material at a plurality ofinterrogation positions.
 23. The method of claim 22, wherein the firsttype of characteristics comprise scattering characteristics, and whereinthe second type of characteristics comprise fluorescent characteristics.